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Integrated Data Acquisition System for Medical Device Testing and Physiology Research in Compliance with Good Laboratory Practices

Steven C. Koenig1, Ph.D., Cary Woolard1, Guy Drew2, Lauren Unger1, Ph.D., Kevin Gillars1, M.S., Dan Ewert3, Ph.D., Laman Gray1, M.D., and George Pantalos1, Ph.D.

1Jewish Hospital Cardiothoracic Surgical Research Institute at the University of Louisville, Department of Surgery, Louisville, KY 402022 US Army Institute of Surgical Research, Fort Sam Houston, TX 78234-63153Department of Electrical and Computer Engineering, North Dakota State University, Fargo, ND 58105

*Funding for this project was provided by a grant from the Jewish Hospital Heart and Lung Institute (Louisville, KY).

Running TitleData Acquisition System

KeywordsData Acquisition, GLP Compliance, Medical Devices, Physiology

CorrespondenceSteven C. Koenig, Ph.D.Associate ProfessorJewish Hospital Cardiothoracic Surgical Research Institute

at the University of Louisville500 South Floyd Street, Room 118Department of SurgeryUniversity of LouisvilleLouisville, KY 40202TEL: (502)-852-7320FAX: (502)-852-1795e-mail: [email protected]

Koenig, et al. ‘Data Acquisition System’ April 17, 2003

ABSTRACT

In seeking approval from the U.S. Food and Drug Administration (FDA) for clinical trial

evaluation of an experimental medical device, a sponsor is required to submit

experimental findings and support documentation to demonstrate device safety and

efficacy that are in compliance with Good Laboratory Practices (GLP). The objective of

this project was to develop an integrated data acquisition (DAQ) system and

documentation strategy for monitoring and recording physiological data when testing

medical devices in accordance with GLP guidelines mandated by the FDA. DAQ

systems were developed as stand-alone instrumentation racks containing transducer

amplifiers and signal processors, analog-to-digital converters for data storage, visual

display and graphical user-interfaces, power conditioners, and test measurement

devices. Engineering standard operating procedures (SOP) were developed to provide

a written step-by-step process for calibrating, validating, and certifying each individual

instrumentation unit and the integrated DAQ system. Engineering staff received GLP

and SOP training and then completed the calibration, validation, and certification

process for the individual instrumentation components and integrated DAQ system.

Eight integrated DAQ systems have been successfully developed that were inspected

by regulatory affairs consultants and were determined to meet GLP guidelines. Two of

these DAQ systems were used in support of 40 of the pre-clinical animal studies to

evaluate the ABIOMED artificial heart. Based, in part on these pre-clinical animal data,

the AbioCor clinical trials began in July 2001. The process of developing integrated

DAQ systems, SOP, and the validation and certification methods used to ensure GLP

compliance are presented in this paper.

Submitted to: Biomed. Instr. & Tech. 1


INTRODUCTION

Scientists, engineers, and clinicians record experimental data to evaluate physiologic

responses with medical devices during acute and/or chronic testing. Assessment of

cardiovascular function on a systems level requires the periodic or continuous

measurement and monitoring of pressures, flows, volumes, and/or electrocardiogram.

The output of the transducers used to measure these physiologic waveforms are

typically in the microvolt or millivolt range, and subsequently require signal conditioning

to provide amplification and/or offset to maximize the input range of the recording

device to optimize data integrity. In the 1960’s, many data acquisition methods involved

recording and analyzing data using strip chart recorders (Maloy 1986, Wilkison 1984).

Although acceptable with proper use and analysis, extrapolation of key physiologic

parameters using this approach can be tedious and time consuming. Experimental data

often consisted of handwritten documentation in laboratory notebooks and/or strip chart

recordings. Over the past several decades, there has been a migration from analog

tape and/or standard strip chart recorders toward digital data acquisition and analysis

systems in which data can be streamed directly to a digital storage device. The

primary advantages to the digital approach is the ability to store large volumes of data,

perform waveform analyses, and by taking advantage of processor speed one can

analyze more data in a faster, more efficient manner. A number of turn-key

instrumentation and software packages are now commercially available to provide data

acquisition and analysis, including BioBench (National Instruments, Austin, TX),

PowerLab (ADInstruments, Grand Junction, CO), ARIA-1 (Millar Instruments,



Houston, TX), DADiSP (DSP Development Corp, Newton, MA), PO-NE-MAH

(Gould Instrument Systems, Valley View, OH ), and WinDAQ (Akron, OH).

To protect the American public against fraudulent products that are consumed either in

or on the body, the Congress passed the Food, Drug, and Cosmetic Act in June 1938.

This Act called for the implementation of regulations for the development, testing, and

marketing of many products. The Medical Device Amendment, passed May 28, 1976,

expanded the scope of the Food, Drug, and Cosmetic Act to include the regulation of all

medical devices. These regulations were to be implemented and carried out by the

U.S. Food and Drug Administration. As a part of this implementation process,

guidelines for the conduct of any experiments to generate data to be submitted to the

FDA seeking product approval were drafted and offered for public comment in 1977.

The final version of this guideline was published in the Federal Register on December

22, 1978 as Title 21 of the Code of Federal Regulations (CFR), Part 58, with the title

Good Laboratory Practice for Non-clinical Laboratory Studies. More commonly referred

to as the GLPs or GLP guidelines, this FDA document has been revised twice, most

recently in January 1999. This article reviews the effort to establish a system for

computer-based data acquisition and analysis that is compliant with GLP guidelines.

According to the Code of Federal Regulations (CFR), all research facilities that conduct

laboratory studies for submission to a regulatory agency such as the US Department of

Health and Human Services and the FDA, are required to establish and maintain a

current management system to assure that GLPs are followed. Title 21 CFR, Part 58,



Good Laboratory Practice for Non-clinical Laboratory Studies describes the standards

for conducting “studies that support or are intended to support applications for research

or marketing permits for products regulated by the FDA, including food and color

additives, animal food additives, human and animal drugs, medical devices for human

use, biological products, and electronic products.” “Compliance with this part is

intended to assure the quality and integrity of the safety and efficacy data filed pursuant

to sections 406,408, 409, 502, 503, 505, 506, 507, 510, 512-516, 518-520, 721, and

801 of the Federal Food, Drug, and Cosmetic Act and sections 351 and 354-360F of the

Public Health Service Act.”

In accordance with 21 CFR, Part 58, specific standard operating procedures (SOP) are

required for each piece of equipment used for data acquisition and monitoring. The

SOP frequently incorporates the specific instructions contained in the equipment

manufacturers’ manual. Details on the methods, materials and schedule for inspecting,

cleaning, maintaining, testing, standardizing and calibrating at the laboratory where the

experiments are being conducted are required, and written records of all of these

procedures must be maintained. Any remedial action that is taken in the event of

equipment failure must also be documented. The designated person(s) responsible for

the performance of each operation described must be qualified and well trained. All

personnel working with the equipment must read, understand and receive in-house

certification to use the equipment.



In response to advances in technology and paperless record keeping, expanded

guidelines were proposed. 21 CFR Part 11 – Final Rule issued in 1997 sets the criteria

under which the FDA will consider electronic records and electronic signatures to be

equivalent to paper records and the more conventional handwritten signatures,

respectively. The FDA defines electronic records as those records created, modified,

maintained, archived, retrieved, or transmitted electronically. Electronic records that

meet the requirements of 21 CFR Part 11.2 may be used in lieu of paper records.

Computer systems (including hardware and software), control processes, and attendant

documentation need to be well organized and readily available because they are

subject to FDA inspection. The process toward achieving GLP compliance with

electronic record keeping (i.e., digital data acquisition) has presented a significant

challenge due to the complexities in developing SOP, validating, and certifying

computer hardware and software. Further, it is quite common for many investigators to

incorrectly assume that a commercially developed data acquisition and analysis

program is GLP compliant. To the best of our knowledge, we are unaware of any

commercial, digital data acquisition systems that are GLP compliant. The objective of

this project was to develop an integrated data acquisition (DAQ) system and

documentation strategy while maintaining quality assurance for monitoring and

recording physiological data during testing of medical devices that meet GLP guidelines

mandated by the FDA. The process for developing, testing, documenting, and certifying

the integrated DAQ system is presented.



METHODS

Data Acquisition Instrumentation Rack. Transducers, amplifiers, and signal processors

were purchased from commercial vendors based on extensive performance testing and

evaluation that has been previously reported. The selection criteria for pressure

measurement was 10 V excitation voltage, fixed gain up to 10 V, frequency

response to 5 kHz, ability to perform multiple physiologic calibration procedures, and

long-term stability and reliability (Reister 1998). Flow measurement instrumentation

was selected by comparing electromagnetic, doppler, and transit-time techniques in a

large animal model to evaluate accuracy, reliability, frequency response, and waveform

morphology (Koenig 1996). Instrumentation amplifiers, signal processors, a custom

developed signal conditioner and distribution unit, analog-to-digital converters and data

storage, visual display and graphical user-interfaces, power conditioners, and test

measurement devices were then integrated in a custom designed, DAQ instrumentation

rack (Figure 1a). This approach provided a stand-alone system that enabled cabling to

be routed in a structured manner that could be visually inspected, well documented, and

minimized electrical noise in the acquired physiological data (Figure 1b). At the base of

the DAQ instrumentation racks are industrial grade wheels that allow easy transport of

these systems to different locations. The DAQ instrumentation racks are comprised of

three key elements: (1) signal conditioning components, (2) communication ports, and

(3) back-up power supply with LED display features. The layout for the DAQ

instrumentation racks was developed using computer-aided design software (AutoCAD,

San Rafael, CA). The CAD designs (Figure 2) were sent to an outside vendor (Premier

Metal, Bronx, NY) for fabrication of the DAQ rack housing.



(Figures 1-2)

The signal conditioning components of the DAQ instrumentation rack include a chassis

with six pressure amplifiers (Ectron Model 428, San Diego, CA ), 2-channels of flow

(Triton Technologies, San Diego CA or Transonics, Ithaca, NY), and 2-channels of ECG

(Gould Instruments, Cincinnati, OH. The low-level analog output (V or mV) from these

amplifiers and signal processors is fed into a 16-channel signal conditioning and

distribution unit (to be described later). These analog data are routed through an

analog-to-digital (A/D) accessory (BNC-2090, National Instruments, Austin, TX)

mounted to the DAQ instrumentation rack, and converted to digital format via an A/D

board (AT-MIO-16E-10, or PCI-MIO-16XE-10, National Instruments, Austin, TX) housed

inside a desktop computer (Micron, Boise, ID) and displayed in real-time on the

computer monitor also mounted in the DAQ instrumentation rack. The analog data may

also be displayed on a variety of precision test and measurement instrumentation

devices including a digital multi-meter (DMM, Fluke model 45, Carrollton, TX ) and/or

digital storage oscilloscope (Tektronix model 340A, Beaverton, OR). The amplifiers,

signal processors, and precision test measurement instrumentation devices were fitted

with heavy duty extension slides (Premier Metal, Bronx, NY) mounted to tapped panel

mounting holes on the DAQ rack housing frame set at 17¾” standards.

Two interface panels are located on one side of the DAQ instrumentation rack (Figure

1c). One interface panel provides 16-channels of analog input and 16-channels of

analog output via BNC connectors. The other interface panel includes LPT1 for

printing, COMM1 for RS-232, a category-5 Internet access connector, and an auxiliary



input for future communication applications. Additional features of the DAQ

instrumentation rack include up to 2 hours of full load battery power back up via an

uninterruptable power supply (Best, Necedah, WI ) and large LED display modules

(Simpson, Elgin, IL). The UPS provides clean power and prevents loss of study data

due to unexpected power surges or power outages. The large LED display modules

provide real-time heart rate, mean arterial pressure, and/or cardiac output that

physicians can easily view at a glance from across the operating table.

Variations of the described DAQ instrumentation rack have been developed in support

of different application requirements. Specifically, DAQ systems were designed with

medical isolation and medically approved amplifiers and signal processors for clinical

intraoperative measurements and monitoring (Figure 3a) that are not required for animal

testing, precision test measurement instrumentation for engineering development

(Figure 3b), and standard instrumentation for universal data collection (Figure 3c). The

clinical monitoring DAQ system includes electrical isolation to minimize risk of

accidental injury to the patient during intraoperative data collection in clinical operating

rooms, catheterization laboratories, or other appropriate hospital settings. The clinically

rated DAQ system (38”h x 22”w x 29”d, 250 lbs) has a chassis with up to eight pressure

and/or ECG amplifiers that are isolated to Association for the Advancement of Medical

Instrumentation (AAMI) standards (Gould Instruments, Cincinnati, OH). In place of a

large desktop computer, a notebook computer (Tecra 8100 Toshiba, New York, NY)

with an A/D card (DAQCard™-AI-16XE-50, National Instruments, Austin, TX) is used.

The notebook computer affords portability of the data beyond the clinical setting. The



engineering development DAQ system (70”h x 27”w x 29”d, 400 lbs) includes a digital

storage oscilloscope for design and development projects. A universal data collection

DAQ system (78”h x 27”w x 29”d, 500 lbs) provides general data collection capabilities

from a variety of external signal conditioners and/or medical monitoring devices in

support of non-clinical studies.

(Figure 3)

Signal Conditioning and Distribution Unit. A key component of the integrated DAQ

system was the development of a 16-channel signal conditioning and distribution (SCD)

unit to drive multiple peripheral monitoring and recording devices without significant loss

of signal strength and integrity. The SCD unit was also designed with finite fixed gain

and offset to maximize A/D input range of peripheral devices, and low-pass filters to

remove electrical noise and prevent aliasing. Specifically, the design criteria per

channel was defined as follows:

Input Impedance = 10 K Negative Offset = up to -4 VDC (1.0 mV)

Output Load Impedance ≥ 2 K Positive Offset = up to 4 VDC (1.0 mV)

Zero setting = 0 VDC (1.0 V) Pos/Neg gain = 1x, 2x, 3x, 4x, 5x (0.1 %)

Inverter = -1x (1 mV) Low pass filter = 60 Hz (24 dB/octave)

A component view of the main amplifier driver for each channel consisting of five

amplifier stages is shown in Figure 4. The analog input signal (J1) is initially fed into a

differential input amplifier (U6-AD620AN) that can be configured to operate in single-

ended or differential mode (Analog Devices, Norwood MA). The second stage consists

of positive or negative offset and zero adjust networks that are switch selectable (SW1-

1 to SW1-3). These networks also include voltage regulators (U2-MC78L05ACP and

U3-MC79L05ACP) to minimize conducted/radiated external electrical noise (Motorola,



Austin, TX). For example, the negative offset network includes a resistor combination

(R12-R3-R11) that can be configured to provide up to -4 VDC offset. The offset and zero

networks are then fed into a second amplifier (U1-AD620AN, Analog Devices, Norwood

MA). The third stage provides antialiasing with low pass filters (U4-D74L4B60Hz) that

have a cutoff frequency of 60 Hz with a 24 dB/octave roll off (Frequency Devices,

Haverhill MA). Assuming a minimal sampling rate of 400 Hz, which is common for most

medical applications, then by the Nyquist Criteria (sampling frequency greater than

twice the cutoff frequency of the filter) the physiological data will not be distorted in gain

and phase due to aliasing. The user also has the option to invert (SW2) the filtered

output before it is fed into a third amplification stage that provides user-selectable fixed

gain steps (SW3-1 to SW3-4) from 1 up to 5 in steps of 1. This gain stage allows

the user to optimize the resolution of the data by maximizing the input range of the

peripheral monitoring/recording device. The output of stage three is then fed through a

series of buffer drivers containing precision bipolar amplifiers (U7-AD704JN) that can

drive multiple output devices (Analog Devices, Norwood MA).

(Figure 4)

The 16-channel SCD unit is wired into the integrated DAQ instrumentation rack to

provide additional signal conditioning and to distribute physiological analog signals to

multiple output devices. The back panel of the SCD contains a single row of BNC input

connectors and three rows of BNC output connectors aligned in 16 columns,

representing 16 channels of signal conditioning. In other words, each channel of the

SCD has a column of BNC connectors for each input signal and three outputs. In

addition to the 164 matrix, there is a column of 3 BNC connectors that allow any of the



16 output channels to be distributed to any of three precision test measurement devices

(i.e., digital multimeter, oscilloscope, etc.) that are user-selectable. The front panel of

the SCD contains 3 rows of user-select switches and LEDs aligned in 16 columns

(Figure 5). Subsequently, each channel represents a column of three user-select

switches that enable the conditioned signal output to be distributed to one of three

peripheral monitoring/recording output devices.

(Figure 5)

The front panel switches have been configured such that only one output channel per

row of switches can be routed to a peripheral monitoring/recording output device.

Additionally, the switch enable scheme was configured to allow multiple switches to be

turned ON, however, only the switch corresponding to the highest channel number will

be enabled. This can be confirmed visually by the LED corresponding to each channel

and output monitor device channel. For example, if channels 2 and 7 are switched ON

for monitor output device 1 (i.e., multimeter), then only the signal conditioned output

from channel 7 will be enabled and it’s corresponding LED illuminated. This

configuration allows the user to easily check the conditioned output for a large number

of signals without constantly flipping switches ON and OFF with the possibility of

missing a recording for a particular channel. For example, during calibration recordings

for 6 channels of pressure, the user turns ON the switch for output channel 1 to record

the output voltage on a DMM then repeats the procedure for output channels 2-6

without having to turn their corresponding switches OFF. Subsequently, this provides a

form of error checking by allowing the user to visually confirm that each channel has

been properly selected.



Data Acquisition Software. Since 1994, the authors have been developing a data

acquisition program for analog-to-digital conversion, real-time graphical display, and

storage of cardiovascular hemodynamic data in support of non-GLP experimental

protocols. The Cardiovascular Data Acquisition Software (CDAS) program (Drew 2000,

Drew 2002) was developed in LabVIEW (National Instruments, Austin, TX), an industry-

standard programming development package commonly used by many

mathematicians, engineers, and scientists. It is a graphically oriented programming

environment that enables development of indicators and controls for real-time data

acquisition compatible with industry-standard analog-to-digital (A/D) hardware (National

Instruments, Austin, TX). The CDAS data acquisition program is configured to run

using four menu-driven screen modes. In mode 1, Measurement and Automation

(National Instruments, Austin TX) is used to assign channel names (i.e., Aortic

Pressure), identify analog input channels (i.e.,channel 1), convert physical input values

to physiologically equivalent units (i.e., 0-2 V = 0-200 mmHg), identify data acquisition

device, and analog-to-digital conversion format (i.e., non-reference single-ended input)

as shown in Figure 6.

(Figure 6)

The user can document the experimental data by annotating fields in the Program

Profile Menu screen (mode 2, Figure 7). Documentation for experimental data sets

include: (1) Data File Parameters to assign a filename and length of data set; (2) File

Header Information to annotate laboratory, organization, study title, subject number,

date of experiment recording, IACUC/IRB protocol number (medical ID number), DAQ

operator, and filename (extension automatically includes date yy/mm/dd and time data



collected); and (3) DAQ Channel Setup to annotate abbreviations for individual channel

names assigned in Measurement and Automation (mode 1), which can be configured to

display data in a variety of formats. Other user-selectable options in mode 2 include the

ability to simultaneously record two separate data sets (i.e., two test subjects, Figure 8),

select fixed data collection epochs (i.e., 30 second files) and/or continuous data

recording (i.e., on-off toggle control), and/or load a previously defined program set-up

file. Indicators and pop-up warning menus provide real-time user feedback in mode 2 to

ensure no errors have been inadvertently made during the configuration process. Upon

successful completion of the set-up and configuration processes, the “run profile”

control can be selected to initiate waveform monitoring and data collection (mode 3).

(Figures 7-8)

Following “run profile” a continuous waveform chart display of up to 16 channels (one

subject) or 8 channels (two subjects) can be initiated (Figure 8). Selected patient

parameters can be monitored continuously and/or stored in automatically incremented

data files (i.e., one data file recording of 30 seconds length every hour for 48 hours).

Additional documentation for each data set can be logged in a “Notes” indicator. An

indicator also identifies whether the continuous (i.e., on-off switch) or epoch data (i.e.,

30 second file) function has been selected and illuminates when enabled. A split screen

feature enables simultaneous monitoring and/or data collection from two different

experiments. There is an overlay feature that allows multiple waveforms from the same

experiment to be displayed in the same graph (i.e., overlay Aortic and Left Ventricular

Pressure). A “freeze” indicator allows the user to stop continuous display and study

individual waveform characteristics without interrupting data collection. An exit indicator



allows the user to return to the Program Profile Menu.

A Data Viewer option (mode 4) allows the user to retrieve and review previously

recorded data sets. The header information and ASCII data for each channel are

automatically displayed. The entire data set or individual epochs can then be replayed

through data display graphs. Indicators located below the data display graphs identify

starting and ending data points and length of data set displayed. ASCII data sets can

easily be imported into a spreadsheet (i.e., Excel) or loaded in a data analysis package.

GLP Compliance Implementation. The development and extensive testing of the DAQ

systems alone are not sufficient to meet GLP standards mandated by the FDA. Further,

it is incorrect to assume automatic compliance by purchasing individual instrumentation,

integrated systems, and/or data acquisition and analysis software from a commercial

vendor. Documentation consisting of standard operating procedures, certification of

testing, calibration, maintenance, and validation of instrumentation, and a quality

assurance unit are required to develop, monitor and audit the conduct of the study. The

documentation must be readily available for FDA inspectors enabling them to determine

whether procedures have been followed to ensure study integrity. The documentation

and quality assurance processes are described next.

Standard Operating Procedures. A standard operating procedure (SOP) is a written set

of instructions for completing a specific task or operating a specific piece of equipment

that has completed a rigorous review and been signed as approved by the author,



supervisor, documentation coordinator, quality assurance manager, and facility

reviewer. The SOP pertaining to the individual instrumentation units and the integrated

DAQ system contain written instructions with procedural methods, materials, schedules

of inspection, cleaning, maintenance, testing, calibration, and/or standardization.

Instrumentation SOP assign designated personnel, list materials and equipment,

provides instructions for inspection, calibration, maintenance, and certification, and

contingency plans to complete the task. Personnel must document their qualifications

through education, experience and training records and for each individual SOP they

are responsible for using. A sample engineering instrumentation SOP is presented in

the Appendix.

Calibration and Maintenance Procedures. All pieces of equipment and instrumentation

are calibrated and maintained as defined by their corresponding SOP. All in-house and

off-site calibration and maintenance is documented and duplicated in Calibration and

Maintenance notebooks, and entered into a certified GLP compliant database for the

laboratory (The Calibration Manager® Database, Blue Mountain Quality Resources,

State College, PA). The Calibration Manager® Database is validated periodically to

ensure effective functionality of the software. Calibration and maintenance labels are

generated and affixed on the front of all instrumentation for quick visual inspection. In

the event of a failed calibration or maintenance check a Failed Calibration Data Integrity

Report is filled out identifying the studies effected, impact on studies, and recommended

course of action. Any resulting repair, maintenance, and subsequent re-calibration



and/or repair are documented before the piece of equipment or instrumentation is

released for use.

Validation Testing and Certification. A critical step toward achieving GLP compliance of

the DAQ system is the validation of the individual measurement instrumentation and the

integrated system. This is accomplished using regression, stress and performance

testing methods that are documented and certified. The individual instrumentation

components of the DAQ system were tested and certified according to their individual

standard operating procedures (SOP), as described earlier. The integrated DAQ

system containing each of these validated and certified components was then tested as

a stand-alone unit. First, a GLP compliant voltage standard (DVC 8500, Calibrators,

Inc., Mansfield, MA) was used to generate static analog input voltage steps in finite

increments from –10 V to + 10 V (range of A/D converters). The displayed and

recorded voltages were compared to the voltage of the data recorder as well as

readings taken from a GLP compliant digital multimeter (Fluke 45 DMM, Carrolton, TX).

Second, a GLP compliant function generator (Tektronix CFG 280, Gaithersburg, MD)

was used to generate square, sawtooth, and sinusoidal waveforms of varying amplitude

(10 V) and frequency (1-1000 Hz), and the displayed and recorded waveforms

compared to the settings of the function generator. Third, a GLP compliant patient

simulator (medSim 300B, Dynatek Nevada, Carson City, NV) was programmed to

produce static (0, 40, 80, 100, and 200 mmHg) and dynamic pressure waveforms (atrial,

ventricular, and arterial) of varying amplitudes (0, 40, 80, 100, and 200 mmHg) and

heart rates (30, 60, 80, 120, 160, 200, and 240 bpm). The displayed and recorded



waveforms were compared to the settings of the patient simulator. Test procedures

were performed for short (24-hours) and long (one-week) evaluation periods. The

experimental results for all test conditions were then documented using test procedure

and validation forms archived in our GLP storage facilities. GLP QAU personnel

performed audit validation testing procedures and support documentation, for

compliance with GLP guidelines. Any discrepancies found during the validation testing

were documented, a course of action recommended, the actions were implemented,

and validation re-testing were conducted and documented.

RESULTS

In 1998, the Jewish Hospital Cardiothoracic Surgical Research Institute at the University

of Louisville (UofL) established a GLP program that includes an in-house Quality

Assurance Unit (QAU). All laboratory personnel received extensive GLP and SOP

training by regulatory affairs consultant (Kathleen Zajd, Prologue Research

International, Westerville, OH) to aid in the Institute’s development of the GLP program.

Engineering staff completed the calibration, validation, and certification process for the

individual instrumentation components and integrated DAQ systems. Eight integrated

DAQ systems have been successfully developed and audited by several quality

assurance specialists (NAMSA, Northwood, OH) and were determined to meet GLP

guidelines. These GLP compliant DAQ systems have successfully supported industry-

sponsored and federally funded research projects for the past three years. We continue

to maintain an active GLP program, performing periodic reviews of our SOP and

support documentation to ensure compliance.



For example, our GLP program has been instrumental in contributing to the pre-clinical

animal studies (Figure 9) required for the ABIOMED AbioCor™ totally implantable

replacement heart (Danvers, MA). Those efforts resulted in FDA approval and initiation

of the multi-center clinical trial for the AbioCor™ resulting in the world’s first two clinical

implants at Jewish Hospital (Louisville, KY). In support of this study, discrete

experimental data points (i.e., heart rate, and systolic/diastolic blood pressure) were

displayed using two DAQ systems outfitted with medical monitoring instrumentation

(Hewlett-Packard medical monitor, Andover, MA). The data were transcribed manually

onto data record forms that were entered into a GLP-validated database developed by

Advertek, Inc. (Louisville, KY). The signed and dated hardcopy printouts have been

identified as the "raw data" and are maintained in conventional archives to support the

submitted study reports. The data acquisition and analysis software currently used for

non-GLP studies is approaching full compliance with the FDA’s regulations pertaining to

electronic records and electronic signatures.

(Figure 9)

DISCUSSION

The concept of designing an integrated DAQ system arose from the need to consolidate

measurement instrumentation in already overcrowded surgical suites and post-

operative holding facilities and the desire to optimize the data acquisition process. The

introduction of federal regulations that pertain to electronic records motivated us to

reassess development and documentation procedures for data acquisition to satisfy

compliance requirements used in GLP laboratory studies. Accomplishing the objective

of developing a compliant customized data acquisition system would allow us the



unique opportunity to provide comprehensive support to research investigators seeking

FDA approval for non-clinical laboratory safety studies.

Investigators at the Jewish Hospital Heart and Lung Institute and other academic

institutions include surgeons, physicians, physiologists, scientists, and engineers. They

actively conduct medical research designed to characterize new surgical techniques,

test innovative medical devices, and evaluate pharmacological agents. Investigators

require accurate data collection of physiological measurements of cardiac, systemic,

and pulmonary function for post-processing analyses. Laboratory studies must comply

with GLP standards for FDA submission of study data and approval for clinical trials.

Approximately 25 academic institutions with membership in the international Society of

Quality Assurance (SQA) are reported to be involved in GLP studies (Hancock, 2002)

that could benefit from an integrated GLP compliant data acquisition system. The

FDA’s release of guidelines for electronic data recording in 1997 provides the

opportunity to implement electronic data recording and documentation strategies, with

many attractive features over current techniques that are limited to reporting discrete

data points and archiving written documentation. The primary features of electronic

data recording and documentation are the ability to record and analyze continuous

waveforms, analyze larger data sets in a more efficient manner (less labor intensive),

document and archive data, and improve accuracy of experimental results by

minimizing measurement error. With advances in computer technology and information

management techniques, we affirm that an integrated data acquisition system with

digital data acquisition and analysis software capabilities for GLP testing of medical



devices will provide investigators with a valuable research capability that will meet FDA

guidelines for electronic data recording.

CONCLUSION

The design of integrated DAQ systems and the step-by-step process for developing the

support documentation and quality assurance program required to meet FDA guidelines

for GLP compliance is presented in this paper. Advances in computer technology

combined with the FDA’s recently released guidelines for electronic data recording and

record keeping provide the opportunity to improve the efficiency and integrity of digitally

acquired experimental data while reducing resource requirements and expense. Our

group has developed eight integrated DAQ systems for animal, clinical, and engineering

applications that meet GLP guidelines, including two systems used to support the

successful pre-clinical testing of the AbioCor artificial heart. We welcome anyone

interested in developing electronic data collection and storage systems to contact us.

We believe the future for pre-clinical testing of medical devices seeking FDA approval is

with electronic data acquisition and analysis strategies.



REFERENCES

1. Drew GA and SC Koenig. Biomedical patient monitoring, data acquisition, and playback with LabVIEW. Chapter 2 (pp 92-98): In LabVIEW for Automotive, Telecommunications, Semiconductor, Biomedical, and other Applications. Prentice Hall PTR, Upper Saddle River, NJ, 2000.

2. Drew, G. A. and Koenig, S. C., “Biomedical Patient Monitoring, Data Acquisition, and Playback with LabVIEW®,” in Virtual Bio-Instrumentation: Biomedical, Clinical, and Healthcare Applications in LabVIEW®, Olansen, J. B. and Rosow, E., 180-186, Prentice Hall, 2002.

3. Hancock, S., Meeting the Challenges of Implementing Good Laboratory Practices Compliance in a University Setting. Qua.l Assur. J. 6, 15-21, 2002.

4. Koenig SC, CA Reister, J Schaub, RD Swope, DL Ewert, and JW Fanton. Evaluation of transit-time and electromagnetic flow measurements in a chronically-instrumented non-human primate model. J. Invest. Surg. 9(6):455-461, 1996.

5. Maloy L and RM Gardner. Monitoring systemic arterial blood pressure: Strip chart recording versus digital display, Heart Lung 15, 627-635 (1986).

6. Reister C, SC Koenig, J Schaub, DL Ewert, RD Swope, and JW Fanton. Evaluation of dual-tip pressure catheters during chronic 21-day implantation in goats. Med. Eng. & Phys., 20:410-417, 1998.

7. Wilkison, DM, KC Preuss, and DC Warltier. A microcomputer-based package for determination of regional and global cardiac function and coronary Hemodynamics, J. Pharmacol. Methods 12, 59-67 (1984).



LIST OF FIGURES

Figure 1. Photographs of an integrated data acquisition (DAQ) system illustrating

location of (a) signal conditioning components, (b) electronic cabling

layout and power conditioning, and (c) communication ports.

Figure 2. Computer aided design of an integrated DAQ system.

Figure 3. Photographs of three multi-functional integrated DAQ systems for (a)

clinical intraoperative measurements and monitoring, (b) engineering

development, and (c) universal data recording applications.

Figure 4. Schematic for one channel of the signal conditioning and distribution

(SCD) unit. Each channel has five stages: (1) differential mode selection,

(2) positive/negative offset and zero network, (3) antialiasing filter, (4)

invert signal selection, and (5) buffering.

Figure 5. Illustration of front panel display for signal conditioning and distribution

(SCD) unit containing 16 columns and 3 rows of ON/OFF switches and

LEDs.

Figure 6. Measurement and Automation (mode 1) to map physical (i.e., volts) to

physiological units (i.e., mHg), and assign analog-to-digital (A/D) device

and input mode (i.e., non-reference single-ended).



Figure 7. Program Profile (mode 2) for documenting experimental data, assigning

waveforms, configuring graphical display, and enabling data collection

options.

Figure 8. Medical monitoring, waveform display, and data recording graphical user

interface (mode 3).

Figure 9. Application of integrated DAQ system used in support of an animal study

to evaluate an implanted cardiovascular device.



Figure 1.


(a) (b) (c)


Figure 2.



Figure 3.

(a) (b) (c)



Figure 4.



Figure 5.



Figure 6.



Figure 7.



Figure 8.

Overlay Select Channel Name Mean Value Freeze Select Exit Graphs andReturn to ProgramMenu

SubjectName/Number

Next Data SetSequenceNumber

Epoch Data Set Save

Data Set Notesand Comments

Mean Pressureand FlowDisplay Select

When selected, 2nd subject controlContinuousData Save



Figure 9.



APPENDIX

SOP F11 REV 01 COPY 01 ELECTRICAL CALIBRATION OF

THE ECTRON MODEL 428 AMPLIFIER

EFFECTIVE DATE: ________

WRITER: S. C. KOENIGPREVIOUS UPDATE: 06/10/99

1.0 PURPOSE The purpose of this Standard Operating Procedure (SOP) is to describe the procedure for calibrating an Ectron model 428 amplifier.

2.0 SCOPEThis SOP pertains to electronics personnel who are authorized to operate an Ectron model 428 amplifier. The Ectron model 428 amplifier is a precision, chopper-stabilized dc amplifier with a selectable-voltage excitation power supply. The Ectron model 428 amplifier is primarily used for amplification and signal conditioning of pressure transducers (i.e. Millar micromanometer catheters) for measuring cardiac and circulatory pressures. It will be calibrated in-house annually.

3.0 DEFINITIONS

3.1 None

4.0 REQUIRED MATERIALS

4.1 Components

4.1.1 Ectron Model 428 Amplifier and Accessories

4.2 References

4.2.1 Certificate of Calibration for Ectron model 428 amplifier

4.2.2 User’s Manual for Ectron model 428 amplifier

4.2.3 SOP F22, Electronic Calibration

4.2.4 SOP F23, Electronic Equipment Maintenance

4.3 Attachments

4.3.1 Not Applicable



5.0 SOP METHODS

5.1 Inspection

5.1.1 CAUTION : The Ectron model 428 amplifier should only be used in non-human applications, unless proper electrical isolation techniques have been established. Use of the Ectron model 428 amplifier in human applications could result in serious injury or death to the patient and/or operator as a result of microshock and/or macroshock.

5.1.2 The Ectron model 428 amplifier should be checked for proper calibration annually (refer to SOP F22, Electronic Calibration).

5.1.3 Prior to use of the Ectron model 428 amplifier, the last recorded calibration date (labeled on control unit) should be verified.

5.1.4 Prior to use of the Ectron model 428 amplifier, the system (control unit and accessories) should be inspected for contaminants (i.e., dirt, blood, etc.) and any visual damage (i.e., broken wires, broken display, etc.).

5.2 Cleaning

5.2.1 CAUTION : Do not use chemicals containing benzine, benzene, toluene, xylene, acetone, or similar solvents.

5.2.2 CAUTION : Do not use abrasive cleaners on any portion of the Ectron model 428 amplifier.

5.2.3 If the Ectron model 428 amplifier requires cleaning, use a soft cloth dampened in a solution of mild detergent and water. Do not spray cleaner directly on the instrument, since it may leak into the cabinet and cause damage.

5.3 Maintenance

5.3.1 When the Ectron model 428 amplifier is not in use, all components (control unit and accessories) should be cleaned and properly stored.

5.3.2 If any physical damage to the Ectron model 428 amplifier (control unit and/or accessories) is observed, it should be sent to the engineering section along with written documentation (refer to SOP F23, Electronic Equipment Maintenance).



5.3.3 Certified engineering staff should refer to Chapter 5, pages 5-1 to 5-12 of the Ectron model 428 amplifier User’s Manual for identifying and completing appropriate maintenance procedures (also see the SOP F23, Electronic Equipment Maintenance).

5.3.4 Repairs called in to the Manufacturer require a RMA number before shipping equipment out for servicing.

5.4 Testing

5.4.1 A series of performance tests may be applied to the Ectron model 428 amplifier, as part of maintenance procedures or if engineering staff suspect a device is out of calibration, by referring to Chapter 5, pages 5-1 to 5-12 of the Ectron model 428 amplifier User’s Manual.

5.4.1.1 If performance tests show device failure, the device may be sent to Ectron, Corp. for servicing.

Contact: Ectron, Corp.8159 Engineer RoadSan Diego, CA 92111-1980Ph: (800)-732-8159Fax: (619)-278-0372e-mail: [email protected]: http://www.ectron.com

5.5 Calibration

5.5.1 If an Ectron model 428 amplifier is out of calibration, it should be sent to the engineering section (refer to SOP F22, Electronic Calibration).

5.5.2 Certified engineering staff should refer to Chapter 5, pages 5-1 to 5-12 of the Ectron model 428 amplifier User’s Manual for identifying and completing appropriate calibration procedures (also refer to SOP F22, Electronic Calibration).

5.6 Certification

5.6.1 Verification of electrical calibration of Ectron model 428 amplifier should be performed by a certified technician or engineer who has been properly trained on these procedures as defined by SOP F22, Electronic Calibration.

5.6.2 Ectron model 428 amplifier calibration certification should be maintained on file as defined by SOP F22, Electronic Calibration.



5.6.3 In-house documentation of requests to Ectron for electrical maintenance and/or calibration of an Ectron model 428 amplifier should be maintained on file as defined by SOP F22, Electronic Calibration and/or the SOP F23, Electronic Equipment Maintenance.

6.0 PERSONNEL RESPONSIBLE FOR ASSURING COMPLIANCE

6.1 Documentation Coordinator- The Documentation Coordinator is responsible for maintaining all GLP-related documentation, files, and archives.

6.2 Engineering Support Staff- Engineering support staff are responsible for adhering to all guidelines as specified in the SOPs pertaining to Engineering.

6.3 Institute Director- The Institute Director is responsible for ensuring overall compliance with GLPs and SOPs.

6.4 QAU Manager- The QAU Manager is responsible for periodically monitoring all procedures, and reporting all findings.

6.5 Study Director- The Study Director is responsible for ensuring that all personnel under his/her supervision are properly trained, are familiar with, and follow all applicable SOPs pertaining to his/her study.

7.0 CONTINGENCIES

7.1 When personnel find circumstances that do not permit compliance with this SOP, they shall immediately consult their supervisor who determines what, if any, follow-up is needed.

8.0 APPROVAL

_______________________________________________________________________Documentation Coordinator Date

______________________________________________________________________Institute Director Date

QAU Manager Date

______________________________________________________________________Writer Date


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